During the first phase of the AMDCC our group at TJU studied the decorin KO diabetic mouse. Our hypothesis was that decorin acts as an endogenous protective factor by inhibiting active TGF-b. We found that decorin is indeed protective, as decorin KO mice had accelerated kidney disease and surprisingly increased mortality. Based on our results, the AMDCC investigators as a group chose the decorin KO diabetic mouse as a leading success during the 1st funding period. Of major mechanistic interest, we found that decorin KO diabetic mice that died exhibited evidence of renal insufficiency and low plasma adiponectin levels, months prior to mortality. This is similar to the human clinical condition. Low adiponectin levels are a powerful biomarker of increased cardiovascular morbidity and mortality in patients with kidney disease. Additionally, the decorin KO mice had increased NADPH oxidase (Nox4) expression in the kidney which may contribute to more severe nephropathy. In the next phase of the AMDCC, we propose test the following hypotheses. 1. Deficiency of adiponectin in combination with lack of decorin leads to enhanced lethality and diabetic nephropathy and 2. Increased Nox4 in vascular smooth muscle cells enhances diabetic nephropathy and the vascular complications of diabetic kidney disease. We propose to generate new diabetic mouse models by crossing adiponectin KO mice with decorin KO mice and by generating mice transgenic for smooth muscle Nox4 using the SM22 promoter. Diabetes will be induced by crossing with Akita mice. These mice will be characterized for diabetic nephropathy and cardiovascular disease. Both new models will be fully characterized for diabetic nephropathy. More importantly, we propose a series of interventional studies to test the causal role of TGF-b, adiponectin, and Nox4 in the pathogenesis of accelerated diabetic nephropathy. Key features we will focus on include matrix accumulation, renal function, autoregulation, and mortality. The proposed studies are directly related to the human condition, in which TGF-(, adiponectin, and Nox4 are key biomarkers for worse disease, but their pathogenetic role is unproven. Our findings will advance our mechanistic understanding of diabetic nephropathy and vascular disease and may lead to better biomarkers and novel treatments.